Fms-like tyrosine kinase 3 (FLT3), which is also known as FLK-2 (fetal liver kinase 2) and STK-1 (stem cell kinase 1), plays an important role in the proliferation and differentiation of hematopoietic stem cells. FLT3 receptor kinase is expressed in normal hematopoietic cells, placenta, gonads, and brain. However, this enzyme is expressed in acute myeloid leukemia cells in approximately 90% of acute myeloid leukemia (AML) patients and in acute lymphoblastic leukemia cells in a fraction of acute lymphoblastic leukemia (ALL) patients. This enzyme can also be found on cells from patients with chronic myeloid leukemia in lymphoid blast crisis.
It has been reported that FLT3 kinase is mutated in 30% of acute myeloid leukemia (AML) and in a subset of acute lymphoblastic leukemia (ALL) as well (Gilliland et al., Blood 2002, 100, 1532-1542; Stirewalt et al., Nat. Rev. Cancer 2003, 3, 650-665). The most common activating mutations in FLT3 are internal tandem duplications (ITD) found within the juxtamembrane region. The FLT3 ITD mutation has been associated with poor prognosis (Frohling et al., Blood 2002, 100, 4372-4380). The second most frequent activating mutation of FLT3 is the missense mutation in the tyrosine kinase domain, mainly at D835 within the activation loop of the tyrosine kinase domain (Yamamoto et al., Blood 2001, 97, 2434-2439). In addition, many non-mutated FLT3 patients show evidence of FLT3 activation. The association of FLT3 mutations with poor clinical outcome and the therapeutic effects observed in early stage clinical trials with first generation FLT3 inhibitors strongly implicate FLT3 as an important target for small molecule intervention in AML.
More than a dozen known FLT3 inhibitors are being developed and some have shown promising clinical effects against AML (Levis et al. Int. J. Hematol. 2005, 82, 100-107). It has been reported that some of small-molecule FLT3 inhibitors are effective in inducing apoptosis in cell lines with FLT3-activating mutations and prolonging survival of mice that express mutated FLT3 in their bone marrow cells (Levis et al., Blood 2002, 99, 3885-3891; Kelly et al., Cancer Cell 2002, 1, 421-432; Weisberg et al., Cancer Cell 2002, 1, 433-443; Yee et al., Blood 2002, 100, 2941-2949).
Despite the success in identification of small molecules that inhibit protein tyrosine kinases, there continues to be an effective method of using or administering such compounds, particularly to humans having AML and ALL, including compounds useful for the treatment of FLT-3 mediated diseases. Methods with improved therapeutic index, i.e, where adverse or unwanted effects of therapy are reduced while efficacy is maintained, are sought.